Elimination of methylation marks at lysines 4 and 9 of histone 3 (H3K4 and H3K9) of spermatozoa alters offspring phenotype

2017 ◽  
Vol 29 (4) ◽  
pp. 740 ◽  
Author(s):  
Serafín Pérez-Cerezales ◽  
Priscila Ramos-Ibeas ◽  
Angela Lopez-Cardona ◽  
Eva Pericuesta ◽  
Raúl Fernandez-Gonzalez ◽  
...  
Keyword(s):  
Heat Stress ◽  
Transgenic Mice ◽  
Transgenic Mouse ◽  
Fetal Development ◽  
Methylation Level ◽  
Movement Coordination ◽  
Epigenetic Marks ◽  
Histone 3 ◽  
Conditional Transgenic Mouse ◽  
Mature Spermatozoa

The contribution of the contents of spermatozoa to the development of the embryo is currently being considered wider than was previously thought. Recent findings point to the participation of epigenetic marks present in the retained histones of mature spermatozoa on embryo and fetal development. Here we created a novel conditional transgenic mouse that expresses lysine (K) demethylase 1a (Kdm1a) during spermatogenesis when the testicles are subjected to heat stress. Using these animals under these conditions we were able to reduce the methylation level of histone 3 at lysines 4 and 9 (H3K4 and H3K9, respectively) in mature spermatozoa. The offspring of these transgenic mice were followed for correct development and growth after birth. We found that the offspring of males expressing Kdm1a suffered 20% of reabsorptions at Day 15 after implantation (vs 0.3% in the control). In addition, 35% of the offspring sired by these males showed some kind of abnormality (suckling defects, lack of movement coordination, dropping forelimbs, abnormal body curvature, absence of eyes, gigantisms and neuromuscular defects) and 25% died before postnatal Day 21. Some abnormalities were maintained to adulthood. These results show that alteration of epigenetic marks present in the retained histones of mature spermatozoa affect fetal development and have phenotypic consequences in the newborn.

scholarly journals Functional and structural connectome properties in the 5XFAD transgenic mouse model of Alzheimer’s disease

2018 ◽  
Vol 2 (2) ◽  
pp. 241-258 ◽  
Author(s):  
Shelli R. Kesler ◽  
Paul Acton ◽  
Vikram Rao ◽  
William J. Ray
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Transgenic Mice ◽  
Transgenic Mouse ◽  
Amyloid Beta ◽  
Molecular Mechanisms ◽  
Diffusion Tensor ◽  
Transgenic Mouse Model ◽  
Structural Connectome

Neurodegeneration in Alzheimer’s disease (AD) is associated with amyloid-beta peptide accumulation into insoluble amyloid plaques. The five-familial AD (5XFAD) transgenic mouse model exhibits accelerated amyloid-beta deposition, neuronal dysfunction, and cognitive impairment. We aimed to determine whether connectome properties of these mice parallel those observed in patients with AD. We obtained diffusion tensor imaging and resting-state functional magnetic resonance imaging data for four transgenic and four nontransgenic male mice. We constructed both structural and functional connectomes and measured their topological properties by applying graph theoretical analysis. We compared connectome properties between groups using both binarized and weighted networks. Transgenic mice showed higher characteristic path length in weighted structural connectomes and functional connectomes at minimum density. Normalized clustering and modularity were lower in transgenic mice across the upper densities of the structural connectome. Transgenic mice also showed lower small-worldness index in higher structural connectome densities and in weighted structural networks. Hyper-correlation of structural and functional connectivity was observed in transgenic mice compared with nontransgenic controls. These preliminary findings suggest that 5XFAD mouse connectomes may provide useful models for investigating the molecular mechanisms of AD pathogenesis and testing the effectiveness of potential treatments.

scholarly journals Transplantation of Adipose-Derived Stem Cells Alleviates Striatal Degeneration in a Transgenic Mouse Model for Multiple System Atrophy

2020 ◽  
Vol 29 ◽  
pp. 096368972096018
Author(s):  
Christine Chang ◽  
Jen-Wei Liu ◽  
Bo Cheng Chen ◽  
Zhe Sheng Jiang ◽  
Chi Tang Tu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mice ◽  
Multiple System Atrophy ◽  
Transgenic Mouse ◽  
Neurodegenerative Disorder ◽  
Ex Vivo ◽  
Transgenic Mouse Model ◽  
Intracerebral Injection ◽  
Nigrostriatal Pathway ◽  
Striatal Degeneration

Patients with multiple system atrophy (MSA), a progressive neurodegenerative disorder of adult onset, were found less than 9 years of life expectancy after onset. The disorders include bradykinesia and rigidity commonly seen in Parkinsonism disease and additional signs such as autonomic dysfunction, ataxia, or dementia. In clinical treatments, MSA poorly responds to levodopa, the drug used to remedy Parkinsonism disease. The exact cause of MSA is still unknown, and exploring a therapeutic solution to MSA remains critical. A transgenic mouse model was established to study the feasibility of human adipose-derived stem cell (ADSC) therapy in vivo. The human ADSCs were transplanted into the striatum of transgenic mice via intracerebral injection. As compared with sham control, we reported significantly enhanced rotarod performance of transgenic mice treated with ADSC at an effective dose, 2 × 105 ADSCs/mouse. Our ex vivo feasibility study supported that intracerebral transplantation of ADSC might alleviate striatal degeneration in MSA transgenic mouse model by improving the nigrostriatal pathway for dopamine, activating autophagy for α-synuclein clearance, decreasing inflammatory signal, and further cell apoptosis, improving myelination and cell survival at caudate-putamen.

scholarly journals Fos-related antigen-1 transgenic mouse as a model for systemic sclerosis: A potential role of M2 polarization

2019 ◽  
Vol 4 (2) ◽  
pp. 137-148
Author(s):  
Hidekata Yasuoka ◽  
Yuen Yu Angela Tam ◽  
Yuka Okazaki ◽  
Yuichi Tamura ◽  
Koichi Matsuo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Systemic Sclerosis ◽  
Transgenic Mice ◽  
Pressure Gradient ◽  
Transgenic Mouse ◽  
Tricuspid Regurgitation ◽  
Mononuclear Cells ◽  
M2 Macrophages ◽  
Wild Type ◽  
M2 Polarization

Objectives: To investigate the systemic sclerosis–related phenotype in fos-related antigen-1 transgenic mice and its underlying mechanisms. Methods: Lung and skin sections of constitutive fos-related antigen-1 transgenic mice and wild-type mice were examined by tissue staining and immunohistochemistry. The tricuspid regurgitation pressure gradient was measured by transthoracic echocardiography with a Doppler technique. To assess the impact of fos-related antigen-1 expression on macrophage function, bone marrow–derived mononuclear cells were derived from mice that expressed fos-related antigen-1 under the control of doxycycline and wild-type littermates. These bone marrow–derived mononuclear cells were induced to differentiate into macrophages with or without doxycycline, and analyzed for gene and protein expression. Finally, lung explants obtained from systemic sclerosis patients and control donors were subjected to immunohistochemistry. Results: The lungs of fos-related antigen-1 transgenic mice showed excessive fibrosis of the interstitium and thickening of vessel walls, with narrowing lumen, in an age-dependent manner. The tricuspid regurgitation pressure gradient was significantly elevated in fos-related antigen-1 transgenic versus control mice. Increased dermal thickness and the loss of subdermal adipose tissue were also observed in the fos-related antigen-1 transgenic mice. These changes were preceded by a perivascular infiltration of mononuclear cells, predominantly consisting of alternatively activated or M2 macrophages. Overexpressing fos-related antigen-1 in bone marrow–derived mononuclear cell cultures increased the expression of M2-related genes, such as Il10, Alox15, and Arg1. Finally, fos-related antigen-1-expressing M2 macrophages were increased in the lung tissues of systemic sclerosis patients. Conclusions: The fos-related antigen-1 transgenic mouse serves as a genetic model of systemic sclerosis that recapitulates the major vascular and fibrotic manifestations of the lungs and skin in systemic sclerosis patients. M2 polarization mediated by the up-regulation of fos-related antigen-1 may play a critical role in the development of systemic sclerosis.

scholarly journals Tamoxifen-inducible cardiac-specific Cre transgenic mouse using VIPR2 intron

2020 ◽  
Vol 36 (1) ◽  
Author(s):  
Hyun Jung Chin ◽  
So-young Lee ◽  
Daekee Lee
Keyword(s):  
Transgenic Mice ◽  
Transgenic Mouse ◽  
Gene Function ◽  
Regulatory Region ◽  
Genetically Engineered ◽  
Specific Gene ◽  
Specific Expression ◽  
Genetically Engineered Mouse Models ◽  
Reporter Mice ◽  
Vasoactive Intestinal Peptide Receptor

Abstract Genetically engineered mouse models through gene deletion are useful tools for analyzing gene function. To delete a gene in a certain tissue temporally, tissue-specific and tamoxifen-inducible Cre transgenic mice are generally used. Here, we generated transgenic mouse with cardiac-specific expression of Cre recombinase fused to a mutant estrogen ligand-binding domain (ERT2) on both N-terminal and C-terminal under the regulatory region of human vasoactive intestinal peptide receptor 2 (VIPR2) intron and Hsp68 promoter (VIPR2-ERT2CreERT2). In VIPR2-ERT2CreERT2 transgenic mice, mRNA for Cre gene was highly expressed in the heart. To further reveal heart-specific Cre expression, VIPR2-ERT2CreERT2 mice mated with ROSA26-lacZ reporter mice were examined by X-gal staining. Results of X-gal staining revealed that Cre-dependent recombination occurred only in the heart after treatment with tamoxifen. Taken together, these results demonstrate that VIPR2-ERT2CreERT2 transgenic mouse is a useful model to unveil a specific gene function in the heart.

scholarly journals Overexpression of spermidine/spermine N1-acetyltransferase under the control of mouse metallothionein I promoter in transgenic mice: evidence for a striking post-transcriptional regulation of transgene expression by a polyamine analogue

1999 ◽  
Vol 338 (2) ◽  
pp. 311-316 ◽  
Author(s):  
Suvikki SUPPOLA ◽  
Marko PIETILÄ ◽  
Jyrki J. PARKKINEN ◽  
Veli-Pekka KORHONEN ◽  
Leena ALHONEN ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Transgenic Mice ◽  
Transgenic Mouse ◽  
Cell Injury ◽  
Mrna Level ◽  
Transgenic Animals ◽  
Ultrastructural Changes ◽  
Mouse Line ◽  
Transgenic Mouse Line ◽  
Polyamine Analogue

We recently generated a transgenic mouse line overexpressing spermidine/spermine N1-acetyltransferase (SSAT) gene under its own promoter. The tissue polyamine pools of these animals were profoundly affected and the mice were hairless from early age. We have now generated another transgenic-mouse line overexpressing the SSAT gene under the control of a heavy-metal-inducible mouse metallothionein I (MT) promoter. Even in the absence of heavy metals, changes in the tissue polyamine pools indicated that a marked activation of polyamine catabolism had occurred in the transgenic animals. As with the SSAT transgenic mice generated previously, the mice of the new line (MT-SSAT) suffered permanent hair loss, but this occurred considerably later than in the previous SSAT transgenic animals. Liver was the most affected tissue in the MT–SSAT transgenic animals, revealed by putrescine overaccumulation, significant decrease in spermidine concentration and > 90% reduction in the spermine pool. Even though hepatic SSAT mRNA accumulated to massive levels in non-induced transgenic animals, SSAT activity was only moderately elevated. Administration of ZnSO4 further elevated the level of hepatic SSAT message and induced enzyme activity, but not more than 2- to 3-fold. Treatment of the transgenic animals with the polyamine analogue N1,N11-diethylnorspermine (DENSPM) resulted in an immense induction, more than 40000-fold, of enzyme activity in the liver of transgenic animals, and minor changes in the SSAT mRNA level. Liver spermidine and spermine pools were virtually depleted within 1–2 days in response to the treatment with the analogue. The treatment also resulted in a marked mortality (up to 60%) among the transgenic animals which showed ultrastructural changes in the liver, most notably mitochondrial swelling, one of the earliest signs of cell injury. These results indicated that, even without its own promoter, SSAT is powerfully induced by the polyamine analogue through a mechanism that appears to involve a direct translational and/or heterogenous nuclear RNA processing control. It is likewise significant that overexpression of SSAT renders the animals extremely sensitive to polyamine analogues.

An enhancer region determines hSP-B gene expression in bronchiolar and ATII epithelial cells in transgenic mice

2003 ◽  
Vol 284 (3) ◽  
pp. L481-L488 ◽  
Author(s):  
Li Yang ◽  
Angela Naltner ◽  
Allison Kreiner ◽  
Dong Yan ◽  
Angelynn Cowen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Transgenic Mice ◽  
Transgenic Mouse ◽  
Lung Development ◽  
Alveolar Type ◽  
Transcriptional Level ◽  
Lacz Gene ◽  
Type Ii ◽  
Enhancer Region

Regulation of the surfactant protein B gene (SP-B) is developmentally controlled and highly tissue specific. To elucidate the SP-B gene temporal/spatial expression pattern in lung development at the transcriptional level, a transgenic mouse model line carrying the human SP-B (hSP-B) 1.5-kb 5′-flanking regulatory region and the lacZ gene was established. Expression of hSP-B 1.5-kb lacZ gene started at the onset of lung formation [embryonic day 9 (E9)] and was restricted to epithelial cells throughout prenatal and postnatal lung development. In the adult lung, hSP-B 1.5-kb lacZ gene expression was restricted to bronchiolar and alveolar type II epithelial cells. In lung explant culturing studies, the hSP-B 1.5-kb lacZ gene was highly expressed in newly formed epithelial tubules during the respiratory branching process. In a second transgenic mouse line, an enhancer region, which binds to thyroid transcription factor-1, retinoic acid receptor, signal transducers and activators of transcription 3, and nuclear receptor coactivators (SRC-1, ACTR, TIF2, and CBP/p300), was deleted from the hSP-B 1.5-kb lacZ gene. The deletion abolished hSP-B lacZ gene expression in bronchiolar epithelial cells and significantly reduced its expression level in alveolar type II epithelial cells in transgenic mice.

huGTPCH Expressing S+S-Antilles Mice Have Reduced Gardos Channel Activity, Endothelin-1 Expression, and Endothelin Receptor A and B Expression, While Total Biopterin and Percent Tetrahydrobiopterin Are Increased

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 537-537
Author(s):  
José R. Romero ◽  
Adriana Muniz ◽  
Ashley Hale ◽  
Nicholas J. Alp ◽  
Alicia Rivera ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mice ◽  
Transgenic Mouse ◽  
Vascular Tone ◽  
Receptor Expression ◽  
Channel Activity ◽  
Endothelin 1 ◽  
Gardos Channel ◽  
Generating Capacity ◽  
Arginine Supplementation

Abstract An imbalance in the ratio between nitric oxide synthase (NOS) and its essential co-factor, tetrahydrobiopterin (BH4), leads to a loss of NO generating capacity and a shift to superoxide production, resulting in a vicious cycle in which BH4 is oxidized and more superoxide is generated. Low NO and hypoxia have been shown to regulate endothelin-1 (ET), an endogenous vasoconstrictor and regulator of vascular tone. There is evidence that BH4 levels can be regulated by ET that is reported to be abnormally high in sickle cell disease (SCD). We have demonstrated that NOS levels are elevated while arginine levels are decreased in sickle transgenic mice. We hypothesized that increasing BH4 bioavailability, even in the absence of arginine supplementation, would ameliorate stresses resulting from NOS dysfunction and would mimic some aspects of arginine supplementation and ameliorate some of the complications of SCD. We studied a sickle transgenic mouse model that was generated by crossing a transgenic mouse expressing human GTP-cyclohydrolase I (huGTPCH), the rate-limiting enzyme in BH4 production, with S+S-Antilles sickle transgenic mice that we have used to study the effect of arginine supplementation on Gardos channel activity and ET expression. We demonstrate that BH4 levels are increased in sickle transgenic mice expressing huGTPCH, and that this is correlated with reduction of Gardos channel activity and ET and ET receptor expression. We measured Gardos channel activity in freshly isolated red blood cells from S+S-Antilles mice and found that Gardos channel activity was decreased in huGTPCH expressing S+SAntilles mice by 63% (from 4.35±0.43 FU to 2.63±0.65 FU in huGTPCH expressors, p<0.01, t-test) which is slightly larger than the decrease previously reported with arginine supplementation (58%) of S+S-Antilles mice without huGTPCH expression. Using RT-PCR we demonstrated that ET and ET-receptor A and B expression were reduced in lung tissue, a major producer of ET, versus that observed in S+S-Antilles mice without the huGTPCH transgene (from 1.84-fold±0.02 to 1.23±0.02, 1.41-fold±0.02 to 0.41±0.02, and from 1.38-fold±0.02 to 0.67±0.02, p<0.05, 0.02, 0.03, respectively). S+S-Antilles mice have an increase of ET and ET-receptor A and B expression versus C57BL of 1.84-fold, 1.41-fold, and 1.38-fold, respectively. We measured total biopterin and percent BH4 in heart and liver of S+S-Antilles mice with and without huGTPCH. In heart, S+SAntilles-huGTPCH mice versus S+S-Antilles had increased percent BH4 (to 0.75±0.02 from 0.46±0.02 pmol/mg protein, p<0.001) and total biopterin was increased 3-fold. In liver, S+S-Antilles-huGTPCH mice versus S+S-Antilles had increased percent BH4 (to 0.30±0.02 from 0.19±0.07 pmol/mg protein, p<0.05) and total biopterin was increased 2.5-fold. In conclusion, BH4 dysregulation is observed in sickle transgenic mice and expression of huGTPCH increased total biopterin and percent BH4 in our sickle mouse model. ET has a profound effect on vascular tone and the reduction of ET mRNA and Gardos channel activity in huGTPCH expressing mice supports the conclusion that the altered BH4 levels observed are physiologically relevant. Thus our observations suggest that BH4 supplementation may ameliorate some of the pathology of SCD.

scholarly journals The cytoplasmic NPM mutant induces myeloproliferation in a transgenic mouse model

Blood ◽  
2010 ◽  
Vol 115 (16) ◽  
pp. 3341-3345 ◽  
Author(s):  
Ke Cheng ◽  
Paolo Sportoletti ◽  
Keisuke Ito ◽  
John G. Clohessy ◽  
Julie Teruya-Feldstein ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mouse Model ◽  
Transgenic Mice ◽  
Transgenic Mouse ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Transgenic Mouse Model ◽  
Acute Myeloid

Abstract Although NPM1 gene mutations leading to aberrant cytoplasmic expression of nucleophosmin (NPMc+) are the most frequent genetic lesions in acute myeloid leukemia, there is yet no experimental model demonstrating their oncogenicity in vivo. We report the generation and characterization of a transgenic mouse model expressing the most frequent human NPMc+ mutation driven by the myeloid-specific human MRP8 promoter (hMRP8-NPMc+). In parallel, we generated a similar wild-type NPM trans-genic model (hMRP8-NPM). Interestingly, hMRP8-NPMc+ transgenic mice developed myeloproliferation in bone marrow and spleen, whereas nontransgenic littermates and hMRP8-NPM transgenic mice remained disease free. These findings provide the first in vivo evidence indicating that NPMc+ confers a proliferative advantage in the myeloid lineage. No spontaneous acute myeloid leukemia was found in hMPR8-NPMc+ or hMRP8-NPM mice. This model will also aid in the development of therapeutic regimens that specifically target NPMc+.

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